antifungal therapy Flashcards
(32 cards)
Why should you care about antifungal therapy?
The number of immunocompromised patients at risk for invasive fungal infection (IFI) is large
Hematology and oncology patients
Solid organ transplants
Rheumatology, GI patients on biologics
This number is expected to increase acutely in SHR in the near future
Allo-Stem Cell Transplant program
HIV epidemic
What was the antifungal therapy before 1990?
AMPHOTERICIN B!!!!!!!!!!! FOR EVERYTHING!!!!!!!!!!!
What is special about amphotericin B? how should you administer it? What are the toxicities of it?
Discovered in 1950s
Still broadest spectrum agent available
Almost always administered IV
Toxicities:
Infusion-related = “shake & bake” premedication
Nephrotoxicity, marrow suppression
What type of ampho. B preparations are there?
Amphotericin B deoxycholate
Lipid-complexed formulations:
amphotericin B lipid complex
(ABLC /Abelcet)
liposomal amphotericin B
(L-AMB /AmBisome)
What is the mechanism of action of amphotericin B?
Binds to ergosterol in the fungal cell membrane
Altered membrane permeability with resulting leakage of cellular components
What is AMPs spectrum of activity?
- candidiasis, cryptococcosis
- histoplasmosis, coccidioidomycosis, blastomycosis
- Aspergillosis
- zygomycosis (mucormycosis)
- sporotrichosis, trichosporidiosis, fusariosis, phaeohyphomycosis
What are the toxicities of AMB?
Nephrotoxicity
Dose dependent
Concomitant agents
Less with lipid formulations
Infusion related
Fever, rigors predominate
Differences between the formulations
With the lipid formulation of AMB. there were less patients with hindered glomerular function.
What are the cost issues with AMB deoxycholate and lipid formulations?
Amphotericin B deoxycholate:
Usual dose 40-80 mg/day = $40-60
Lipid formulations: Usual daily dose 5 mg/kg $ hundreds per day $800-$1000/day 5 years ago Dropping significantly due to new alternatives
What are the recommendations for use for Lipid AmB. in saskatoon health region?
Invasive fungal infections refractory to conventional AmB
Patient intolerant of conventional AmB
Renal dysfunction
- Pre-existing or developing on AmB
Selected difficult to treat pathogens
What are the marketed systemic antifungal agents?
amphtericin B, Azoles, Echinocandins (e.g. caspofungin)
What are the targets of these antifungals?
Membrane ergosterol
Direct damage
- Polyenes
- Amphotericin B, Nystatin
Synthesis inhibited
- Azoles
- Keto-, Flu-, Itra-, Vori- and Posaconazole
- Allylamine
- Terbinafine
Cell wall Glucan synthesis
- Echinocandins
- Caspo-, Mica- and Anidulafungin
- Several other targets under investigation
- Nucleoside analogue
- Flucytosine (5-FC)
What are invasive mycoses?
Invasive candidiasis
Despite safer therapies, significant crude and attributable mortality rates remain
Invasive Aspergillosis
Treatment outcomes poor due to severely immunocompromised patients
Recent emphasis on prophylaxis
Miscellaneous mycoses
Zygomycetes, many uncommon moulds
Cryptococcus neoformans, C. gattii
What still remains to be the easiest stemic antifungal to use in invasive candidiasis? and why, or why not?
Fluconazole remains the easiest systemic antifungal to use
Well absorbed orally, IV uncomplicated
Well tolerated, few significant drug interactions
BUT resistance can be an issue
What is fluconazole?
Water soluble
Oral tabs, solution
IV
Excellent safety profile
Activity
- Most yeasts
- Moulds variable
What are the echinocandins?
Semisynthetic derivatives of Echinocandin B, naturally synthesized by A. nidulans
Inhibit β-(1,3)-D-glucan synthase
in vitro and animal activity:
Candida spp. (including azole-resistant strains)
Aspergillus spp.
Not Cryptococcus species
What is caspofungin?
Approved in Canada in 2004
Treatment of Invasive Aspergillosis in patients refractory to or intolerant of other therapies
Empirical therapy for presumed fungal infection in febrile, neutropenic patients
Treatment of Invasive Candidiasis
Candidemia, intra-abdominal abscesses, peritonitis, pleural space infections
Treatment of Esophageal Candidiasis
What is micafungin?
Approved in Canada in 2007:
Candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses (100 mg/d)
Esophageal candidiasis (150 mg/d)
Prophylaxis in patients undergoing hematopoetic stem cell transplantation (50 mg/d)
Major route of elimination is fecal excretion
No adjustments for renal failure, dialysis, mild or moderate liver dysfunction
What is anidulafungin?
Approved in Canada in 2008 for:
Treatment of invasive candidiasis/candidemia in adult non-neutropenic patients
Chemical degredation
No renal clearance or hepatic metabolism
No adjustments, no CYP interactions
What is the word then on invasive candidiasis?
Fluconazole remains the easiest systemic antifungal to use
Well absorbed orally, IV uncomplicated
Well tolerated, few significant drug interactions
BUT resistance can be an issue
Echinocandins As safe as FLU Cover most FLU resistant strains might be more effective even for susceptible strains Cost is dropping (competition)
What is invasive aspergillosis/?
Invasive aspergillosis ~ 60% case-fatality rate 1990’s US hospital discharge data: 10,000 hospitalizations, 2000 deaths, $633M Cumulative 12 mo. incidence @ 12 centers Auto SCT 0.5% Matched, related allo 2.3% Mismatched, related allo 3.2% Unrelated donor SCT 3.9%
New procedures likely will increase risk
Nonmyeloablative conditioning, T-cell depletion
What is the treatment of choice for invasive aspergillosis?
Voriconazole
considered to be the treatment of choice for proven or probable IA
What is voriconazole?
aka Vfend
Twice daily dosing, IV and oral forms
Variable po bioavailability
Most metabolized: CYP2C19
No renal failure adjustment
Voriconazole IV solubilizer accumulates in renal failure
Transient ocular symptoms at time of peak levels
what is voriconazole used for?
Spectrum (in vitro, animals):
Candida spp., including many flu-resistant
Cryptococcus and Aspergillus species
Dimorphic fungi
“Difficult” filamentous organisms Fusarium spp. Trichosporon spp. Pseudallescheria boydii Scedosporium prolificans
What are some indications for use of variconazole?
Canadian approval in 2005:
Invasive aspergillosis
Candidemia in non-neutropenic patients
Invasive candidiasis involving other sites
Dissemination involving skin
Abdomen, kidney, bladder wall, wounds
